Vascular smooth muscle and atherosclerosis: role of isoprenoids and calcium antagonists

Smooth muscle cell (SMC) proliferation in the arterial wall has been implicated as having a central role in hypertension, atherosclerosis, and restenosis after angioplasty. As mevalonate and other intermediates (isoprenoids) of cholesterol biosynthesis are important in stimulating the proliferation of SMC, it was of interest to study the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitors (vastatins) on cholesterol biosynthesis and growth of cultured arterial myocytes. Simvastatin (S) and fluvastatin (F), but not pravastatin (P), decreased the rate of growth of rat vascular SMC. This inhibition, evaluated on the basis of cell numbers, was dose-dependent with IC50 values of 2.8 μM and 2.2 μM for S and F, respectively; P (1 to 500 CLM) was inactive. The inhibition of cell growth (70% decrease) induced by S and F, each at a dose of 3.5 μM, was completely prevented by the addition of 100 CLM of mevalonate and partially (70% to 85%) inhibited by the addition of 10 μM of farnesol and 5 μM of geranylgeraniol, thereby confirming the specific role of isoprenoid metabolites in regulating cell proliferation. Several events involved in the formation of atherosclerotic plaque are mediated by calcium, suggesting that atherogenesis may be affected by calcium antagonists (CAs). It has been observed that verapamil, nifedipine and nifedipine-like derivatives, isradipine, and lacidipine are all active in inhibiting SMC proliferation in culture. These in-vitro effects of S, F, and CAs were paralleled by their ability to inhibit neointimal formation induced by the insertion of a flexible collar around the carotid artery of normocholesterolemic rabbits. In conclusion, the treatment of atherosclerosis may be achieved by direct effects on the processes involved in atheroma formation. This effect may be obtained with compounds already able to modify the major risk factors of atherosclerosis such as hypertension and hypercholesterolemia or, in the future, by new compounds specifically designed as direct antiatherosclerotic drugs.